Manufacture of laevo-1-phenyl-2-methylaminopropanol-1



Patented May 1, 1934 Ni OFFICE.

MANUFACTURE OF LZEVO-l-PHENYL-Z- IVIETHYLA'MINOPROPANOL-l GustavHildebrandt and Wilfrid Klavehn, Mannheim, Germany, assignors, by mesneassignments, to E. Bilhuber, Incorporated, Jersey City; N. J., acorporation of New Jersey No Drawing. Application April 3, 1931, Serial8 Claims.

The naturally occurring ephedrine obtained from the drug is thelav-1-phenyl-2-methylamino-propanol-l. This compound has hitherto beenobtained synthetically only by resolving synthetic racemic ephedrineobtained by various known processes (Nagai & Kanao: Annalen der Chemie,Vol. 470 page 157; German Patent No. 469,782; Skita & Keil: Berichte derdeutschen chemischen Gesellschaft, 'Vol. 62, 1929, page 1142 19 et seq.)into its optical isomers (Nagai & Kanao: Annalen der Chemie, Vol. 470page 157; British Patent No. 297,385; Swiss Patent No. 138,724). Therehas not hitherto been known a process whereby lavo-l -pheny1- 2-methylamino-propanol-l can be synthesized directly.

According to this invention laevo-l-phenyl-Z- methylamino-propanol-l canbe made directly and with a good yield by reducinglwvo-l-phenylpropanol-1-one-2 in presence of methylamine;

alternatively, l-phenylpropanol 1-one-2 may first be condensed withmethylamine and the condensation product subsequently reduced.

The laevo phenylpropanolone use as parent material for the invention maybe obtained according to the method of Neuberg (BiochemischeZeitschrift, Vol. 115, 1921, page 282, and Vol. 128, 1922, page 610),for example by the fermentation of a solution of sugar with yeast in thepresence of benzaldehyde. When the fermentation is ended, thefermentation product, in which is contained the lavo keto-alcohol, isisolated by extraction or distillation and may be reduced as such inpresence of methylamine, or the keto-alcohol may be separated from theproduct and subjected to reduction in presence of methylaminer Theinvention affords a new method for the useful application of laavophenylpropanolone which is easily obtainable by the method of Neu- 40berg, by permitting its conversion intoltevo-lphenyl-2-methylaminopropanol-1.

This direct synthesis of larva-ephedrine has the further advantage thatit does not involve also the production of dextro-ephedrine which is ofno therapeutical value, as is the case in the known processes whichdepend on the resolution ofthe racemic substance.

The following examples illustrate the invention:

Example 1.120 grams of the fermentation product containingphenylpropanolone obtained by extraction with ether (of. BiochemischeZeitschrift Vol. 115, 1921, page 282 et seq.) are allowed to run,without further purification, in the 5 course of about two hours into asolution of 10 ether to the reaction mixture.

In Germany April 8, 1930 contacts with water, it liberates hydrogen andan insoluble aluminium hydroxide is formed. Activated aluminium thusserves as the source of hydrogen for the reaction. When the reaction iscomplete the ethereal solution is filtered and the optically active basewhich has-been formed is extracted from the filtrate by means of diluteacid. The product is worked up in the usual manner. There is obtainedthe hydrochloride of lmvo-lphenyl-2-methylamino-propanol-1 havingamelting point of 214 C., and having the optical rotation given in theliterature. The yield amounts to 25-45 grams of the hydrochloridedepending upon the nature of the parent material.

Example 2.-360 grams of the ether extract containing phenylpropanoloneused as parent material in Example 1, are subjected to distillationunder reduced pressure. 300 grams of the fraction which distils at100-150 C. under a pressure of 14 millimetres are subjected to catalytichydrogenation in presence of colloidal platinum (70 cc. of a solution of1 per cent strength) and 85 grams of a solution of methylamine of 33'per cent strength. It is advantageous to add some When absorption ofhydrogen is complete, the ethereal solution is shakenwith hydrochloricacid and the laevo-lphenyl-2-mcthylamino-propanol-1 is isolated in knownmanner from the hydrochloric acid extract.

The hydrochloride melts at 214 C. and has .the optical rotation given inthe literature. The yield of the hydrochloride amounts to 110 grams.

Example 3.100 grams of leave l-phenylpropanol-1-one-2 isolated by themethod of Neuberg (Biochemische Zeitschrift Vol. 128, 1922, page 611)are dissolved in 200 cc. of ether, 75 grams of a solution of methylamineof 33 per cent strength are added and the whole is shaken for about halfan hour; condensation occurs with evolution of heat. The reactionmixture is then treated with hydrogen in presence of 70 cc.- of acolloidal solution of platinum of 1 per cent strength. The reductionproduct is worked up in the manner indicated in Example 2.

The hydrochloride of laevo-1-pheny1-2-methylammo-propanol-l crystallizesfrom alcohol in the form of coarse prisms having a melting point of214-216" C. The free base melts at C.

We claim:

1. A method for the manufacture oflievo-lphenyl-Z-methylamino-propanol-l which comprises acting upon thereaction product of laval-phenyl-propanol-1-one-2 and methylamine and areducing agent and reducing the condensation product, whilesubstantially avoiding formation of racemic final by-products.

2. A method for the manufacture of1a:vo-lphenyl-Z-methylamino-propanol-1 which comprises acting upon anextract not further purified of a mixture containinglavo-phenyl-propanol-1-one-2 of the kind produced by the fermentation ofa sugarlin presence of benzaldehyde, with methylamine and a reducingagent, while substantially avoiding formation of racemic finalby-products.

3. A method for the manufacture oflaevo-lphenyl-2-methylamino-propanol-1 which comprises condensing adistillate not further purified of a mixture containinglwvo-phenyl-propanol- 1-one-2 of the kind produced by the fermentationof a sugar in presence of benzaldehyde, with methylamine and reducingthe condensation product, while substantially avoiding formation ofracemic final by-products.

4. A method for the manufacture oflaevo-lphenyl-2-methylamino-propanol-l which comprises condensing anextract not further purifled of a mixture containinglaavo-phenyl-prowith methylamine and reducing the condensation product,while substantially avoiding formation of racemic final by-products.

. fermentation of a sugar in presence of benzaldehyde into a solution ofmethylamine in ether in\ 5, A method for the manufacture oflaavo-lphenyl-Z-methylamino-propanol-1 which comprises the steps,running the ethereal extract not further purified of the productobtained by presence of an activated aluminium, water being addedsimultaneously, filtering the ethereal solution when the reaction iscomplete, extracting from the filtrate the optically active base whichhas been formed by means of dilute hydrochloric acid and isolating thehydrochloride of lsevo-lphenyl-Z-methylamino-propanol-1 in the usualmanner, while simultaneously with said steps, substantially avoidingformation of racemic final by-products.

6. A method for the manufacture oflaavo-lphenyl-2-methylamino-propanol-1 which comprises the steps,distilling under reduced pressure the ethereal extract not furtherpurified of the product obtained by fermentation of a sugar in presenceof benzaldehyde, subjecting the fraction which distills at 100150 C.under a pressure of lei millimetres to catalytic reduction in pres--ence of colloidal platinum and methylamine, extracting the etherealsolution with hydrochloric acid and isolating the hydrochloride oflaevo-lphenyl-2-methylamino-propanol-1 in the usual manner, whilesimultaneously with said steps, substantially avoiding formation ofracemic final by-products.

7. A method for the manufacture of lmvo-lpheny1-2-methylamino-propanol-lwhich comprises the steps, condensing lavo-l-phenyl-propanol-1-one-2with methylamine in ethereal solution, treating the reaction mixturewith hydrogen in presence of colloidal platinum, extracting the etherealsolution with hydrochloric acid and isolating the hydrochloride oflazvo-lphenyl-2-methylamino-propanol-l in the usual manner, whilesimultaneously with said steps, substantially avoiding formation ofracemic final by-products.

8. A method for the manufacture of leaveephedrine which comprisestreating laavo-lphenyl-propanol-l-one-2 condensed with methylamine witha reducing agent in the presence of a metallic hydrogenation catalystand reducing the condensation product to form lmvo-l-phenyl-2-methylamino-propanol-1.

GUSTAV HILDEBRANDT. WILFRID KLAVEHN.

